OP0044 CYTOKINE PROFILE, HYPERFERRITINEMIA, AND MULTI-VISCERAL INVOLVEMENT CHARACTERISE MACROPHAGE ACTIVATION SYNDROME COMPLICATING ADULT ONSET STILL’S DISEASE. RESULTS FROM A MULTIDIMENSIONAL EVALUATION
Authors: P. Ruscitti, F. Ursini, O. Berardicurti, F. Masedu, E. Bozzalla Cassione, S. Naldi, I. DI Cola, C. DI Muzio, L. De Stefano, E. DI Nino, F. Sensini, L. Navarini, M. Vomero, S. Bugatti, M. Valenti, E. Mariani, A. Iagnocco, C. Montecucco, R. Giacomelli, P. Cipriani
Journal: Annals of the Rheumatic Diseases (2022)

Background Adult-onset Still’s disease (AOSD) is a rare multigenic autoinflammatory disease of unknown aetiology burdened by life-threatening, such as macrophage activation syndrome (MAS) [1]. Considering the poor outcome of MAS patients, previous works tried to assess predictive factors of its occurrence during AOSD [2-4]. However, an integrated evaluation of clinical features with biomolecules, more reflecting the pathogenic mechanisms of the disease and its complications, is still missing. Objectives To multidimensionally characterise MAS complicating AOSD considering cytokine profile, inflammatory markers, and multi-visceral involvement of the disease. To perform a high-dimensional phenotypic analysis of circulating immune cells in AOSD patients with and without MAS. To assess interferon (IFN)-related pathways in AOSD synovial tissues by a bulky RNA sequencing. Methods The present evaluation was designed to multidimensionally compare AOSD patients with or without MAS, considering cytokine profile, inflammatory markers, and multi-visceral involvement of the disease. Clinical and biologic data were collected and compared in AOSD patients with and without MAS. Sera biomolecules were analysed by Luminex multiplexing technology. Mass cytometry (CyTOF) was used to characterise circulating immune cells. A bulky RNA sequencing was performed in AOSD synovial tissues. Results In this study, 40 consecutive AOSD patients (47.7±15.0 years, 50.0% male gender) were assessed at the time of diagnosis before the administration of any immunosuppressive therapy. Out of those, 14 (35%) patients were complicated by MAS. Paralleling with increases of systemic score and ferritin, MAS patients were characterised by an increased concentration of IL-1α, IL-1β, IL-1Ra, IL-2Ra, IL-6, IL-10, IL-17A, IFN-γ, G-CSF, MCP-1, MIP-1α, SCF. Among these biomolecules, IL-1Ra, IFN-γ, MCP-1, and SCF were correlated with MAS. Combining the discriminatory ability of these data in identifying MAS, the best model was composed by systemic score, ferritin, IFN-γ, and IL-10. This model was characterised by AUC=0.99 (Standard error: 0.008; 95%CI: 0.976–1.000), sensitivity=100%, specificity=95.45%. By CyTOF analysis, AOSD patients, who were complicated or not with MAS were characterised by a significant increase of circulating “classical monocytes” (CD14+CD38+). MAS patients were characterised by a significant reduction of NK cells (CD45RA+CD56dim) than AOSD patients. Finally, the transcriptomic profile, by RNA-sequencing analysis, showed that 3477 among type I, II, and III IFN-related genes (IRGs) were significantly different in AOSD synovial tissues. Conclusion A multidimensional characterisation of AOSD patients was provided suggesting that IFN-γ, IL-10, ferritin, and systemic score discriminated MAS, thus identifying the occurrence of the cytokine storm syndrome. The inflammatory milieu of AOSD and MAS may be associated with a signature of circulating immune cells. Finally, our results about IRGs reinforced the role of IFN-γ in these patients. References [1]Giacomelli R, Ruscitti P, Shoenfeld Y. A comprehensive review on adult onset Still’s disease. J Autoimmun. 2018;93:24-36. [2]Ruscitti P, et al. Macrophage Activation Syndrome in Patients Affected by Adult-onset Still Disease: Analysis of Survival Rates and Predictive Factors in the Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale Cohort. J Rheumatol. 2018;45:864-872. [3]Di Benedetto P, et al. Ferritin and C-reactive protein are predictive biomarkers of mortality and macrophage activation syndrome in adult onset Still’s disease. Analysis of the multicentre Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort. PLoS One. 2020;15:e0235326. [4]Wan L, et al. Total metabolic lesion volume of lymph nodes measured by 18 F-FDG PET/CT: a new predictor of macrophage activation syndrome in adult-onset Still’s disease. Arthritis Res Ther. 2021;23:97. Disclosure of Interests None declared.